Diagnose and Manage Early

and Advance Parkinson

Disease
Thamrin Syamsudin
 Epidemiology of Parkinson
Syndrome
• Incidence
– 5-24/105 worldwide (USA, 20.5/105)
– Incidence of PS/PD rising slowly with aging
population
• Prevalence
– 57-371/105 worldwide (USA/Canada 300/105)
– 35-42% of cases undiagnosed at any time
• Onset
– Mean PS 61.6 years: PD 62.4 years
– Rare before age 30; 4-10% cases before age 40
 Classification of Parkinson
Syndromes in a Community
• Idiopathic PD - 85% of all PS cases
• Neuroleptic-induced parkinsonism (DIP) 7-9%
• MSA (SDS, SND, OPCD) 2.5%
• PSP 1.5%
• Vascular parkinson syndrome 3%
• PS due to MPTP, CO, Mn, recurrent head trauma
is extremely rare
• No new cases of postencephalitic parkinsonism
since 1960s
 Main Biochemical Abnormality
• Marked striatal DA depletion
– “Striatal dopamine deficiency syndrome"
• At death, DA loss > 90%
• <50% DA loss is asymptomatic
 70% DA loss for symptom manifestations
• Severity of DA loss best correlates with
bradykinesia in PD
 Parkinson's Disease Risk Factors
• Definite: Old age
• Highly likely: MZ co-twin with early-onset PD
• Probable: Positive family history
• Possible: Herbicides, pesticides, heavy metals,
proximity to industry, rural residence, well water,
repeated head trauma, etc.
• Possible protective effect: Smoking
Normal Basal Ganglia Functional Anatomy

N o rm a l
C o r te x
C in g u la te S u p p l. M o to r P r e m o to r
P r e fro n ta l S e n so ry P r e m o to r P r e fro n ta l
In s u la r M o to r
+ +

+
S tr ia tu m +
+ T h a la m u s
D2 D1 V A /V L
- +
-
+ = e x c ita to r y
SNc
STN - = in h ib ito r y
+ SNr -
-
- B r a in s te m
+
GPi SC
- +
G Pe -
Function Anatomy of Parkinson’s Disease

P a r k i n s o n ’s D i s e a s e
C o r te x
C in g u la te S u p p l. M o to r P r e m o to r
P r e fr o n ta l S en so ry P r e m o to r P r e fro n ta l
I n s u la r M o to r
+ +

+
S tr ia tu m +
+ T h a la m u s
D2 D1 V A /V L
- +
--
+ = e x c ita to r y
SNc
STN - = in h ib ito r y
++
- SNr - -- B r a in s te m
GPi - SC
-- ++
G Pe ++
 Cause of PD
• Unknown in most cases; not accelerated aging
• Genes
– Mutation of Alpha synuclein gene (chromosome 4q)
identified in one large Italian (Contursi) and 5 Greek
autosomal dominant families
– Mutation of Parkin gene in autosomal-recessive
juvenile parkinsonism
• Environment
– Majority of cases believed caused by environmental
factor(s) but none identified so far
• Genes plus environment?
Environmental Toxin Model: MPTP
• Reproduces all the major motor features of PD

MAO-B
MPTP  MPP+
(in Astrocyte)

• Dopaminergic neuron mitocriondria

• Inhibits NADH-CoQl (Complex I) of mitochondrial
respiratory chain
• ATP production falls
• Cell death
 Hypotheses of SN Pathogenesis
• Apoptosis; mitochondrial?
  oxidative stress,  antioxidant capacity
  iron in neuromelanin,  free radical formation
–  complex I and glutathione in SNc
• Slow or weak excitotoxicity
– ATP loss  Membrane potential  decline persistent
activation of NMDA receptors  calcium influx, nitric
oxide, superoxide, peroxynitrite formation
• Inadequate neurotrophic factor(s)
Preclinical Parkinson's Disease
• No specific clinical markers known
• 4-13% of autopsies in elderly showing incidental
Lewy bodies are regarded as preclinical cases
• Increased risk of neuroleptic parkinsonism
• Duration of preclinical phase unknown (several
years to several decades?)
• PET studies may identify preclinical cases
 Early Signs and Symptoms
Cardinal Other
Characteristics • Micrographia
• Resting tremor • Masked face
• Bradykinesia • Slowing of ADLS
• Rigidity • Stooped, shuffling
• Postural instability gait
• Decreased arm swing
when walking
 Criteria for Diagnosis
• At least two of three: rest tremor,
bradykinesia, rigidity
• Absence of a secondary cause-drugs,
metabolic, etc.
• Definitive diagnosis can only be made by
autopsy
 Differential Diagnosis of PD:
Hereditary disorders associated
with parkinsonism

• Wilson's dicease
• Huntington's disease
• Dentatorubro-pallidoluysial atrophy (DRPLA)
• Machado-Joseph disease (SCA-3)
Differential Diagnosis of PD:
• Secondary Parkinsonism
• Drug-induced
• Toxin-induced
• Metabo!ic
• Structural lesions (vascular parkinsonism, etc.)
• Hydrocephalus
• Infections
 Drug-induced Parkinsonism
• Crucial to rule out since most cases are
reversible
• Careful medication history-list drug names
• Common offending drug types
• Treatment: Stop offending medication
 Metabolic and Infectious Causes of
Parkinsonism
• Metabolic
– Often reversible
– Hypo- or hyper-thyroidism
– Hypo- or hyper-parathyroidism
– Liver failure
– Central pontine myelinolysis
• Infectious
– Post-encephalific
– Creutzfeldt-Jakob disease
– Intectious masses
– HIV
Toxin-induced Parkinsonism
• MPTP
• Carbon monoxide
• Manganese
• Cyanide
 Treatment Options
• Preventive treatment
– No definitive treatment available
• Symptomatic treatment
– Pharmacological
– Surgical
• Non-motor management
• Restorative-experimental only
– Transplantation
– Neurotrophic factors
 Early Management of PD
• Provide symptomatic relief
• Reduce functional disability
• Reduce or delay long-term complications of
drug therapy
– Motor fluctuations
– Dyskinesia
• Slow disease progression:
"neuroprotection"
 Clinical Decision-Making in Early PD

• Disease severity
– Degree of functional impairment
– Impact on quality of life
• Age of patient
– Comorbidities
– Risk of acute drug intolerance
– Risk of long-term complications
 When to Begin Therapy
• Definitive neuroprotective therapy not yet
available
• Timing of symptomatic therapy is
individual
– Degree of functional impairment
– Lifestyle of patient
 Initial Therapy: The Elderly Patient
• Shorter treatment horizon
• Lower risk of long-term complirations
• Higher likelihood of comorbidities
• Levodopa: well tolerated, effective
• Use adjunctive medications cautiously
• Avoid sedating medications
 Initial Therapy: The Young Patient
• Long-term treatment horizon
• Increased risk of long-term complications
• Increased patient responsibilities
• Dopamine agonist monotherapy
• Levodopa-sparing strategies
• Putative neuroprotective strategies
• Role of levodopa is not adequately defined
 Initial Therapy: What is the Chief
Complaint?
Predominant symptoms Clinical Options
No functional impairment Delay therapy

Mild symptoms Amantadine, selegiline

Discrete symptoms Tremor-anticholinergic

Depression--antidepressant
Anxiety-anxiolytic

Functionally disabling symptom Levodopa,dopamine agonist,

COMT inhibitor
 Levodopa: Guidelines in Early PD
• Start low and increase slowly
• Titrate dosage to efficacy (200-600 mg/day)
• Immediate release
– more rapid onset
– shorter duration of benefit
– generic available
• Controlled release
– longer duration of benefit
– some patients prefer less frequent dosing
• Acute side effects: nausea, dizziness, somnolence
Dopamine Agonists: Guidelines in Early PD

• Effective as monotherapy
• Less symptomatic benefit than levodopa
• May delay need for levodopa approx. 12 months
– data up to >3 years has been presented
• Start low and increase slowly
• Titrate to efficacy
– Bromocriptine 7.5-30'mg/day
– Pergolide 1.5-4.5 mg/day
– Pramipexole 1.5-4.5 mg/day
– Ropinirole 3-24 mg/day
• Acute SEs: nausea, dizziness, somnolence, confusion
 Nonpharmacologic Treatments
• Patient/caregiver education
• Physical therapy
• Exercise
• Occupational therapy
• Speech/language therapy
• Diet and nutrition
• Psychosocial interventions
 Education, Support and Counseling

• Patient/caregiver education: newsletters, web

resources
• Support groups: patient, caregivers
– may be appropriate to wait for disability progression
– early-onset patients may desire separate group
• Counseling
– both patient and caregiver/family, assess needs
separately
– anxiety, grief, guilt, anger, isolation, depression
The Course of Parkinson Disease

Complications during
treatment and disease
EARLY SYMPTOMS progressions

DIAGNOSIS

“honeymoon period”

“Lost Paradise”
 Complication during disease
progression in advanced PD

1. Treatment related motor complications

2. Disease-related complications
3. Autonomic dysfunctions
Complications during disease progression in PD

Treatment related complications

Motor fluctuations, dyskinesias, akinetic crises
• Motor fluctuations; dependent on dopaminergic
therapy
– End of dose hypokinesia
• Early morning hypokinesia
• Posprandial hypokinesia
• Nocturnal hypokinesia
• Motor fluctuations; not related to dopamimetic
therapy (unpredictable on/off fluctuation)
First signs of beginning fluctuations
and dyskinesias
• Early morning akinesia
• Loss of sleep benefit (the refreshing
effects of sleep)
• Restlessness of fidgetiness (early signs of
peak dose dyskinesia)
• Tremor as an end dose pattern
Plasma Levodopa level remains within a narrow
therapeutic window during the whole day
 Management of motor fluctuations
(general approaches)

• Reach a continuous dopaminergic

receptor stimulation
– Improve levodopa absorption and transport
– Stabilize levodopa plasma levels
 Therapy of motor fluctuation
End of dose akinesia
• Increse dosage frequency with smaller levodopa
portions
• Combine soluble standard and slow release
levodopa
• Add COMT inhibitor and/or selegiline

Early morning akinesia

• Soluble levodopa “early morning kick”
 Therapy of motor fluctuations

Unpredictable on/off fluctuation

– Add gastrokinetics (domperidone)
– Decrease levodopa dose and increase the
dose of dopamine agonists
– Avoid slow release levodopa preparations
– In longer off periods s.c. apomorphine
Akinetic crises intravenous application of
amantadine or apomorphine
 Therapy of motor fluctuations

Posprandial akinesia
• Levodopa intake 20 min before meal
• Reduction of dietary protein
• Enhance gastric motility (domperidone)
• Duodenal levodopa infusions

Nocturnal akinesia, off-dose dystonia

• Slow release levodopa
• Dopamine agonists with long half time (carbegoline)
• Nocturnal apomorphine infusion
 Therapy of Levodopa induced dyskinesias

• Peak dose dyskinesias

– Reduce single levodopa dose and increase dosage or
dopamine agonists
– Add amantadine
– Switch to monotherapy with high dosed dopamine
agonist?
• Dyphasic dyskinesias
– Reduce single levodopa dose and increase the
frequency of levodopa
– In “off dyskinesia” add dispersible levodopa increase
dosage of dopamine agonists
 Management of motor fluctuations
general approaches
• Add dopamine agonists
• Ergot derivates : bromocriptine, lisuride,
pergolide, carbegoline, dihydroergocriptine)
• Non-ergot derivatives: pramipexol, robintrole
• Neurosurgery
• Application of subcutaneous apomorphine
– Intermittern single dose (2-5 mg)
– Continuous application
 Management of motor fluctuation general
approaches
• Reach a continuous dopaminergic receptor
stimulation:
– Improve levodopa absorption and transport
– Stabilize levodopa plasma levels
• Add COMT inhibitors
• Add MAO-B inhibitors (enhance striatal
dopamine concentration)
• Reduce dietary protein (1g/kg per day)

(Golbe et al 1987, Poewe et al.1987, Marsden 1994, Baas 1996,

Chase 1996, Hause et al 2000, Poewe, Deuschl 2002)
 Prevention of motor fluctuations
• Early combination of levodopa and dopamine
agonists
– Levodopa/lisuride 10 yrs
– Levodopa/bromocriptine, Prado study, 4 yrs
• Monotherapy with dopamine agonists
– Carbegoline vs levodopa, 5 yrs (Rinne et al.1998)
– Ropinirole vs levodopa, 5 yrs (Rascol et al, 1999)
– Pergolide vs levodopa, 3 years (Oertel et al, 2000)
– Pramipexole vs levodopa, 4 yrs (Pk study group,
2002)
• Dopamine agonists in higher doses
 Management of disease related
complications
• Freezing
– Using aids
• Self commands
• Freezing stick
• Metronome
– Training for changing stance
– Postural imbalance
– Training gait reflexes
• Speech difficulties
– Speech training with the “Lee Silverman Method”
• Dysphagia
• Amantadine infusion
 Problems of autonomic dysfunctions

• Orthostatic hypotension (15-20%)

– Midodrine (Jancovic et al.1993, Low et al.1997)
– L-threo-dops (Freeman et al 1999)
• Constipation (80%)
– Plantago afra/oyata
– Macrogols: polyethylenglycol
 Problems of Autonomic Dysfunctions

• Neurogenic bladder disturbance (70-80%)

– Anticholinergic agents: oxybutyrinine,
tolperodine (Abrams et al. 1998)
• Erectile dysfunction (40-50%)
– Sildenafile, apomorphin (O Sullivan, et al. 1998,
Zeslewicz et al 2000)

• Basically drugs that have shown efficacy

in non Parkinson patients
 Surgical therapy in PD
• Thalamotomy
• Pallidotomy
• Deep brain stimulation
• Fetal tissue implantation
• Choroidal artery ligation
 Surgical Ablative Approaches
Selective patients:
• Medically intractable idiopathic Parkinson
• Pallidotomy: effective in patients with
akinesia/bradikinesia, postural instability,
speech disturbance and tremor
• Thalamotomy: rigiditas, drug induced
dyskinesia and tremor
• Target selection: Gpi, STN and Thalamus
 Deep Brain Stimulation (DBS)

• Physiological basic still unclear

• Effect of electrical stimulation in subcortical
structure are likely multifactorial
• Most dependent on stimulation parameter
& location
• Stimulation parameter wether higher
frequencies (>100 Hz) more effective
• Alternative location: Gpe, STN, VIM
 Embrionic tissue transplants in PD

• Many questions remain to be answered

before one can be certain that it can
provide long-term benefit (Fahn,1992)
• Technical and ethical issues are
unresolved
• Porcine fetal cell implants still under
investigation (Ellis,1998)

•Lindvall et al,1990,1002, Freed, 1990, Freeman 1995

 Practical advice for practitioners
• PD, early stage, no interference with ADL:
cerefully explain to patient about his illness, what
to expect. Do not cause undue alarm! Delay
treatment if possible
• PD, early stage, but patient feels something has
to be done: start with non-ergot dopamine
agonist. Explain that this medication will not give
immediate result
• After a certain period of time (years?), as the PD
progresses, levodopa may become necessary.
Use small frequent dosing to delay onset of
dyskinesia
 Advice for practitioners
• If wearing-off has developed, change to
extended release formulation, increase the dose
by about 20%, while decreasing the number of
daily doses by about 30-40%
• In case of dyskinesia: give smaller, more
frequent doses. Pulsatile dopamine-receptor
stimulation may induce changes leading to
motor fluctuations and dyskinesia that
complicates long term L-dopa therapy